Missing Parts? Salamander Regeneration Secret Revealed

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Salamanders can regrow entire limbs and regenerate parts of major
organs, an ability that relies on their immune systems, research
now shows.

A study of the axolotl (Ambystomamexicanum),
an aquatic salamander, reveals that immune cells called
macrophages are critical in the early stages of regenerating
lost limbs. Wiping out these cells permanently prevented
regeneration and led to tissue scarring. The findings hint at
possible strategies for tissue repair in humans.

"We can look to salamanders as a template of what perfect
regeneration looks like," lead study author James Godwin said in
a statement. "We need to know exactly what salamanders do and how
they do it well, so we can reverse-engineer that into human
therapies," added Goodwin, of the Australian Regenerative
Medicine Institute (ARMI) at Monash University in Melbourne.
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In mammals, macrophage cells play an important role in the
immune
system response to injury, arriving at a wound within
two to four days. There, they engulf and digest pathogens, or
infectious particles, and generate both inflammatory and
anti-inflammatory signals for healing.

Now, Godwin and his colleagues have shown that macrophages are
essential for salamanders' superherolike ability to sprout new
limbs. The researchers studied the biochemical processes that
occurred in salamanders at the site of a limb amputation. They
then wiped out some or all of the macrophage cells to determine
whether these cells were essential for regrowing the limbs.

Signals of
inflammation were detected at the wound sites within one
day of the amputations. Unexpectedly, anti-inflammatory signals,
which normally arrive later in mammals recovering from injury,
were also present at that time. Along with these signals, the
researchers detected macrophages at the wound, peaking in number
around four to six days after the injury.

To investigate the role of macrophages in salamander
limb regeneration, the researchers injected the animals with
a chemical substance that destroys or "depletes" these cells. The
macrophage levels were either partially or fully depleted.

Salamanders that had all their macrophages removed failed to
generate new limbs and showed substantial scar-tissue buildup.
Salamanders that had only some of their macrophages could still
regenerate their limbs, but more slowly than normal.

Once the salamanders replenished their macrophage levels, the
researchers re-amputated the animals' limb stumps, which then
fully regenerated at the normal rate. Collectively, these
findings suggest macrophages are essential to the salamanders'
remarkable wound-healing abilities.

Studying the regenerative abilities of salamanders could offer
insight into treating spinal cord and brain injuries in humans,
the researchers say. Furthermore, the knowledge might lead to new
treatments for heart and liver diseases or recovery from surgery,
by preventing harmful scarring.

Macrophages are already known to play a vital role in organ and
tissue development in
mouse embryos. They produce small signaling molecules that
activate other types of cells that promote the growth of new
limbs and the healing of wounds.

Many animals may have a capability for tissue regeneration that
has been turned off as the result of evolution, but it might be
possible to reactivate the process, Godwin said.

The findings were detailed today (May 20) in the journal
Proceedings of the National Academy of Sciences.